title: RNF41 (Nrdp1) controls type 1 cytokine receptor degradation and ectodomain shedding.
abstract: Cytokines, such as interferons, erythropoietin, leptin and most interleukins, signal through type 1 cytokine receptors and activate the canonical JAK-STAT pathway. Aberrant cytokine signalling underlies numerous pathologies and adequate, temporary receptor activation is therefore under tight control. Negative-feedback mechanisms are very well studied, but cellular sensitivity also depends on the number of receptors exposed at the cell surface. This is determined by the equilibrium between receptor synthesis and transport to the plasma membrane, internalisation and recycling, degradation and ectodomain shedding, but the molecular basis of how cells establish steady state receptor levels is poorly understood. Here, we report that ring finger protein 41 (RNF41, also known as E3 ubiquitin-protein ligase Nrdp1) interacts with JAK2-associated cytokine receptor complexes and modulates their cell surface exposure and signalling. Moreover, ectopic expression of RNF41 affected turnover of leptin, leukaemia inhibitory factor and interleukin-6 receptor in a dual way: it blocked intracellular cathepsin-L-dependent receptor cleavage and concomitantly enhanced receptor shedding by metalloproteases of the ADAM family. Receptor degradation and shedding are thus interconnected phenomena with a single protein, RNF41, determining the balance.
authors.affiliation: Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology (VIB), Ghent University, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium.
authors.forename: Joris
authors.initials: J
authors.lastname: Wauman
authors.forename: Leentje
authors.initials: L
authors.lastname: De Ceuninck
authors.forename: Nele
authors.initials: N
authors.lastname: Vanderroost
authors.forename: Sam
authors.initials: S
authors.lastname: Lievens
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
mesh_terms: D002460:Cell Line; D006801:Humans; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D018121:Receptors, Cytokine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018121:Receptors, Cytokine; C452580:RNF41 protein, human; D044767:Ubiquitin-Protein Ligases